Distinguishing Convulsive Syncope from Seizure induced by repetitive Transcranial Magnetic Stimulation (rTMS) - A Case Report

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is FDA cleared for clinical use in treatment-resistant depression and a growing list of other disorders. The clinical uptake of rTMS has been facilitated by its relatively benign side-effect profile compared to other treatment modalities. Seizure is a rare but serious adverse event that has been reported with rTMS, when dosage exceeds safety guidelines or in individuals at increased risk for seizure. Fortunately, most rTMS-induced seizures are typically transient, with no adverse sequelae, but they may lead to treatment discontinuation. Seizure is not the only cause of loss of conscious and abnormal movements induced by rTMS. Convulsive syncope, a more common adverse event that involves loss of consciousness associated with myoclonic movements, can be difficult to differentiate from an rTMS-induced seizure. We report the case of a 52-year-old male with no known seizure risk factors, enrolled in an IRB approved research study who developed what appeared to be a convulsive syncopal episode lasting 10–15 seconds during day-2 of a 30-day rTMS protocol (10Hz, 120% of motor threshold (MT), 4 sec pulse train, 26 second intertrain interval, 3,000 pulses per session), with no adverse sequelae. The patient’s history, screening, physical examination, pertinent laboratory, neurology consult, EEG, and imaging findings are discussed. This case demonstrates that distinguishing between convulsive syncope and rTMS-induced seizure can be a diagnostic challenge. Clinicians and researchers delivering rTMS should be familiar with the risk factors for rTMS-induced seizures and rTMS-induced convulsive syncope, to screen for predisposing factors, and to manage these rare adverse events if they occur.

Introduction

When given within safety guidelines, repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and effective treatment for major depressive disorder (MDD) and other conditions. Its most common side effects are headache and scalp discomfort. Rare side effects include hearing loss, seizures, induction of manic and psychotic symptoms, and syncope. Syncope can be associated with motor movements (convulsive syncope) which can be difficult to differentiate from seizure. Here we report a case of a patient with MDD who developed convulsive syncope during his second treatment with rTMS. Adding to the literature, this illustrates how to differentiate convulsive syncope from seizure in the context of rTMS.

Case Report

The patient was a 52-year-old right-handed White male who had a history of MDD going back to adolescence. His most recent episode started one year prior to presentation. He had a history of generalized anxiety disorder, social anxiety, panic disorder without agoraphobia and specific phobias for needles and heights. At intake he met criteria for generalized anxiety disorder and recurrent MDD based on the Structural Clinical Interview for DSM-V (SCID). He was hospitalized twice for suicide attempts during high school and college. He had prior trials of selective serotonin reuptake inhibitors (SSRIs) including citalopram and sertraline, as well as bupropion and amitriptyline. He had not previously received rTMS or ECT. His medical history was significant for scoliosis with decreased sensation in the extremities. He did not endorse symptoms of mania, psychosis, substance use disorder or obsessive-compulsive disorder. He was enrolled in an institutional review board (IRB) approved research protocol at the NIMH. The aim of the study was to evaluate target engagement using individualized, neuronavigated, functional magnetic resonance image (fMRI)-guided rTMS given simultaneously with a form of cognitive therapy.

At baseline, he screened negative for risk factors for adverse effects from rTMS. He had no personal or family history of seizures, no traumatic brain injury, and was not taking any medication or illicit drug that increased risk of seizure. His physical examination was unremarkable except for decreased sensation and joint position sense in his lower extremities. His initial vital signs showed a blood pressure (BP) = 102/66, respiratory rate (RR) = 16, pulse (P) = 75, oxygen saturation (O2 sat) = 98%, and temperature (T) = 36.6 degrees C. His baseline brain MRI was normal with no masses or lesions. He reported a history of “benign” arrythmia and his initial electrocardiogram (ECG) was significant for sinus bradycardia (HR=56 bpm) with nonspecific ST-segment elevation (2 mm) and tall T-waves (up to 11 mm) in some of the anterior leads (V3-V5) likely representing an early repolarization pattern and a normal variant. Other laboratory measures were within normal limits including C-reactive protein, hepatic panel, lipid panel, serum chemistries, thyroid stimulating hormone, complete blood count, urinalysis, HIV screening, serum folate and B12 level. His psychotropic medication regimen consisted of 30 mg of buspirone at night and 20 mg of escitalopram daily. Patient did not report recent use or current use of any other medication except flonase as needed for seasonal allergy.

rTMS was well tolerated on day 1 and was delivered at 10 Hz, 120% resting motor threshold (RMT), 4 second pulse train, 26 second intertrain interval, and 3000 pulses using a Magventure Magpro X100 stimulator (Magventure, Inc., Alpharetta, GA, USA) with a figure eight coil (A/P, B65). RMT was determined based on the minimum stimulus intensity needed to elicit a motor evoked potential of ≥50μV in peak-to-peak amplitude from the first dorsal interosseus using electromyography (EMG). His RMT was 55% of maximal stimulator output. Neuronavigation was performed using BrainSight (Rogue Research, Canada). The target was selected based on the region of the left middle frontal gyrus that was activated the most in response to goal promoting stimuli following the methods in Luber et al.¹ The TMS coil was held in place by a robotic arm system (Axilum Robotics, France). Except for mild headache and scalp pain, the patient had no adverse sequalae on day 1.

On day 2 of rTMS, his vital signs were T=35.8, BP= 109/71, P=78, RR=19, 02 sat = 98% on room air. He was notably conversational during the first few minutes before starting rTMS. After treatment began, he reported a mild headache on the right side of his head and felt some discomfort with the procedure stating that it was “annoying”, but he wanted to continue. About 5 minutes after reporting the headache, the patient reported feeling dizzy and asked to take a break. rTMS was immediately stopped per his request. At this point, the patient was 14 minutes into the session and had received 28 trains of stimulation. As soon as rTMS was stopped, he lost consciousness, followed by clonic focal movements of facial muscles particularly around the forehead and both upper extremities, and gurgling sounds from the patient’s throat. The episode lasted about 10–15 seconds. Staff moved him from the treatment chair to the floor. He did not fall, hit his head, nor did he incur any serious injuries. He did not recall the events that occurred during loss of consciousness, but recalls being moved from the chair to the floor. Afterwards he regained consciousness and was fully alert. He was oriented to person, place, purpose but the patient had a feeling he was unconscious for a longer duration. Within a few minutes of regaining consciousness, he reported feeling nauseated and light-headed. He had diaphoresis and bit his lip during the episode. He had a small laceration on his lip that did not require stitches. There were no other injuries that were noted in the oral cavity. There was no loss of bowel or bladder control and no confusion. His vital signs after the episode showed orthostatic changes in blood pressure: BP=115/78, P 70 (sitting); BP=99/70, P= 69 (Standing); O2 sat 100%. The code team responded promptly and medical as well as neurological consults were obtained.

The patient was admitted to the neurology inpatient unit for observation and assessment including a detailed neurological exam, serum chemistries, cardiac myotroponins, ECG, brain MRI, and an awake and asleep electroencephalogram (EEG). The detailed neurological exam revealed asymmetric hyperreflexia in his left upper extremity concerning for an atypical Todd’s paralysis. However, the EEG was within normal limits, with no focal, paroxysmal, or epileptiform abnormalities. Upon further questioning, the patient reported having a previous episode of syncope and low blood pressure. He has no history of diabetes, and his serum glucose was normal. His ECG and laboratory work up were unchanged from baseline, except for a mild hyponatremia of 132 mmol/L (Normal range: 136 – 145 mmol/L), most likely a dilutional effect as patient drank a lot of water after the incident, which improved the following day. He was discharged after 12 hours and his neurology exam during a follow up visit the next was normal. While it was impossible to rule out rTMS-induced seizure because EEG was not recorded during the event, the history and clinical manifestations presented in this case were judged by neurology to be most consistent with convulsive syncope due to a lack of a post ictal disorientation, onset of symptoms with headache and diaphoresis in the setting of his history of syncopal episodes and orthostatic hypotension. His rTMS treatment was discontinued as recommended by the neurology team.

Discussion

There have been very few cases of TMS-induced seizures reported in the literature. One study reported standardized risks of about 8/100,000 sessions, but much higher rates of up to 33/100,000 sessions in individuals at higher risk.² As of February 2020, 41 cases of TMS induced seizures have been identified in the literature.² Since then, an additional 12 cases of possible TMS-induced seizures have been reported to the US FDA Manufacturer and User Facility Device Experience (MAUDE) database. Only one case of convulsive syncope with TMS was reported to MAUDE in the last 10 years (not counting the current case). Risk factors for rTMS-induced seizures include: adolescent age, substance use (stimulants, alcohol withdrawal), pre-existing neurological conditions (such as epilepsy, structural brain damage, infarction, demyelinating disease), sleep deprivation, electrolyte abnormalities (hyponatremia, hypocalcemia, hypomagnesemia, hypoglycemia, renal failure/uremia, liver failure), systemic infections, fever and taking medications that may lower the seizure threshold.²

Risk factors for syncope are highly varied and depend on the cause.³ This patient had no risk factors for rTMS-induced seizure but had some predisposing factors that put him at higher risk of syncope (past history of syncope, low blood pressure). Syncope has been reported less frequently than seizure as a result of rTMS. Potential reasons for this may be because it is misdiagnosed as a seizure. Alternatively, because syncope is a less serious complication than seizure, it may be deemed less worthy of report in the literature. The total number of rTMS-induced syncope events is not known. In one study, 29 out of 174 (17%) of the participants reported experiencing a syncope or presyncope (a subjective feeling that one is about to pass out but there is no loss of consciousness) with rTMS but the participants did not report the number of events.⁴ One report of a near syncopal episode was attributed to a specific effect of prefrontal rTMS resulting in parasympathetic overdrive.⁵ When syncope occurs, it is most often associated with myoclonic movements or other motor activity, which can make it difficult to distinguish from a seizure.

Most episodes of syncope and seizures induced by TMS occur during the first three sessions.² The mechanism of syncope induced by rTMS may be related to decreased blood supply to the brain that could occur in the setting of hypotension, bradycardia or hyperventilation resulting in cerebral vasocontraction due to decreased carbon dioxide levels in the brain.⁵ There is also the possibility of syncope due to a vasovagal reaction associated with increased anxiety or psycho-physical discomfort associated with rTMS. Notably, this patient reported feeling some discomfort associated with rTMS in the few minutes preceding his syncope, and he had a history of significant co-morbid anxiety disorders.

It is important to appropriately screen and monitor patients for seizure and syncope. This includes inquiring about risk factors for seizure and syncope before starting rTMS. Warning signs that may precede syncope can also allow early detection and the possibility of aborting a full-blown episode before it occurs. For instance, the mild headache and discomfort the patient reported before the episode, though not specific, could have indicated the onset of symptomatic changes leading to syncope. It is important to investigate and probe for these and other warning signs especially in patients with predisposing factors. Patients should also be observed during the rTMS procedure for any abnormal movements or change in behavior or activity that could indicate a seizure or syncope.

Most of the reported cases of syncope and seizure related to rTMS are brief and most patients recover fully without need for additional treatment. A history of a single rTMS-induced seizure does not confer increased risk of future episodes. Regardless, discontinuing rTMS treatment may be the best course of action as we did with this patient. Additionally, distinguishing between the two is important to ensure patients get the appropriate intervention and follow up. Notable differences include rapid return of consciousness in syncope versus seizures and absence of post-ictal confusion, incontinence, and tongue-biting. Oral frothing and vomiting occur after convulsive syncope as opposed to seizure episodes (Table 1).² Although serum prolactin level measured within 20 minutes after seizure onset is a reliable tool for differentiating epileptic seizures from psychogenic non-epileptic seizures, it is not useful in distnguishing seizures from syncope.⁶ The reports of feeling nauseated, signs of diaphoresis and orthostasis in this patient and the short duration of the episode favor convulsive syncope, whereas elevated blood pressure and tachycardia typically follow a seizure episode.

Table 1:

Distinguishing features between seizure and convulsive syncope

Seizure	Syncope
Triggers are rare	Commonly associated with triggers such as strong pain or emotions, standing
Prodromal symptoms of somatosensory or psychic aura, olfactory hallucinations, and automatisms (e.g., lip smacking)	Prodromal symptoms of presyncope, nausea, visual blurring, epigastric sensation, headache, tinnitus, palpitation, and sweating
Myoclonic jerks prior to LOC	Myoclonic jerks after LOC
Lasts about 1–2 mins	Lasts less than 1 min
Usually associated with elevated BP and HR	Usually associated with low BP and HR
Post-ictal confusion	Rapid recovery
Mostly horizontal eye deviation or blank stare	Mostly vertical eye deviation, rolling back or eyes closed
Other features: lateral tongue biting, incontinence	Other features: vomiting, oral frothing

In conclusion, the absence of increased seizure risk at baseline, the previous history of low blood pressure, syncope, and bradycardia, as well as the characteristic nature of the presentation points more towards convulsive syncope rather than rTMS-induced seizure in this patient. Even though these risk factors are not contraindications for rTMS, they may increase the risk of syncope in patients undergoing rTMS. In addition, the absence of focal, paroxysmal, or ictal activity on the EEG makes rTMS-induced seizure less likely. Availability of personnel and medical resources to intervene if these complications occur should be considered when delivering rTMS.